US3551431A - Isonipecotonitriles - Google Patents
Isonipecotonitriles Download PDFInfo
- Publication number
- US3551431A US3551431A US739194A US3551431DA US3551431A US 3551431 A US3551431 A US 3551431A US 739194 A US739194 A US 739194A US 3551431D A US3551431D A US 3551431DA US 3551431 A US3551431 A US 3551431A
- Authority
- US
- United States
- Prior art keywords
- acid
- isonipecotonitrile
- ether
- solution
- phenylethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 29
- 239000013543 active substance Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 150000003839 salts Chemical class 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 206010011224 Cough Diseases 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 150000003053 piperidines Chemical class 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
- 239000001828 Gelatine Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 229920000159 gelatin Polymers 0.000 description 8
- 235000019322 gelatine Nutrition 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
- 239000006188 syrup Substances 0.000 description 7
- 235000020357 syrup Nutrition 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 150000007522 mineralic acids Chemical class 0.000 description 6
- 150000007524 organic acids Chemical class 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000454 talc Substances 0.000 description 6
- 235000012222 talc Nutrition 0.000 description 6
- 229910052623 talc Inorganic materials 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- QCYIFDAFIXZTQO-UHFFFAOYSA-N lithium;diphenylmethylbenzene Chemical compound [Li+].C1=CC=CC=C1[C-](C=1C=CC=CC=1)C1=CC=CC=C1 QCYIFDAFIXZTQO-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000000954 anitussive effect Effects 0.000 description 3
- -1 arene sulphonic acid esters Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- FSDNTQSJGHSJBG-UHFFFAOYSA-N piperidine-4-carbonitrile Chemical compound N#CC1CCNCC1 FSDNTQSJGHSJBG-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- AAAQKTZKLRYKHR-UHFFFAOYSA-N triphenylmethane Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 AAAQKTZKLRYKHR-UHFFFAOYSA-N 0.000 description 3
- QDNKANVPPGGTHL-UHFFFAOYSA-N 1-(2-phenylethyl)piperidine-4-carbonitrile Chemical compound C1CC(C#N)CCN1CCC1=CC=CC=C1 QDNKANVPPGGTHL-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 150000001339 alkali metal compounds Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940046892 lead acetate Drugs 0.000 description 2
- 239000011981 lindlar catalyst Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000000294 tussive effect Effects 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RIEJCTSZBHZCFP-UHFFFAOYSA-N 1-(3-phenylpropyl)piperidine-4-carbonitrile Chemical compound C1CC(C#N)CCN1CCCC1=CC=CC=C1 RIEJCTSZBHZCFP-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 240000000560 Citrus x paradisi Species 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OWYWGLHRNBIFJP-UHFFFAOYSA-N Ipazine Chemical compound CCN(CC)C1=NC(Cl)=NC(NC(C)C)=N1 OWYWGLHRNBIFJP-UHFFFAOYSA-N 0.000 description 1
- 241001466453 Laminaria Species 0.000 description 1
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920005439 Perspex® Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PKMPMUHWHIIFBJ-UHFFFAOYSA-N piperidin-1-ium-4-carbonitrile;chloride Chemical compound Cl.N#CC1CCNCC1 PKMPMUHWHIIFBJ-UHFFFAOYSA-N 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- UJTRRNALUYKHQE-UHFFFAOYSA-N sodium;diphenylmethylbenzene Chemical compound [Na+].C1=CC=CC=C1[C-](C=1C=CC=CC=1)C1=CC=CC=C1 UJTRRNALUYKHQE-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000004291 sulphur dioxide Substances 0.000 description 1
- 235000010269 sulphur dioxide Nutrition 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
Definitions
- R is allyl or propinyl and their addition salts with inorganic and organic acids, have valuable pharmacological properties, in particular antitussive activity with, at the same time, a favourable therapeutic index.
- the antitussive activity of the compounds of general Formula I for instance the hydrochlorides of I-(Z-phenylethyl)-4-allyl isonipecotonitrile, 1-(2-phenylethyl)-4-(2- propinyl)-isonipecotonitrile, 1 (3-phenylpropyl)-4-allyl isonipecotonitrile and 1-(3-phenylpropyl)-4-(2-propinyl)- isonipecotonitrile, can be demonstrated, e.g., on intravenous administration in the cat by the method according to R. Domenjoz, Arch. exp. Path. und Pharmakol. 215, 19-24 (1952).
- Another method for provingthe antitussive activity is the determination of the tussive irritation in the guinea pig, caused by sulphur dioxide, by subcutaneous or oral administration of the test substances.
- male guinea pigs in a perspex chamber were exposed at atmospheric pressure to an SO /CO /air mixture at a constant ratio of 20 ml.:1.5 litres:l0.5 litres per minute until the onset of cough or for a maximum of 120 seconds. The onset of cough was assessed visually.
- the guinea pigs reacting with cough were put in groups of 6 animals each.
- the new piperidine derivatives of general Formula I and their pharmaceutically acceptable acid addition salts are suitable as active substances for pharmaceutical preparations for the treatment of coughs, particularly for the amelioration and relief of tussive irritation. They can be administered orally, rectally or parenterally to warmblooded animals, particularly mammals.
- an amide of the general Formula II i 1120 CH2 R1 (II) wherein R and R have the meanings given in Formula I is reacted with an agent spliting off water and, if desired, the compound obtained of the general Formula I is converted into an addition salt with an inorganic or organic acid.
- Thinoyl chloride, phosphorus trichloride and phosphorus pentoxide are mentioned as examples of agents which split off water.
- the water is split oif, e.g., by boiling an amide of the general Formula II with thionyl chloride in benzene or chloroform or by heating with phosphorus pentoxide, preferably at temperatures between and 200, or by heating with phosphorus trichloride.
- Formula IV 1120 CHz wherein Y6 represents an alkali metal ion, particularly lithium ion and R, has the meaning given in Formula I, in an inert organic solvent with a reactive ester of allyl alcohol or 2-propin-1-ol and, if desired, converting the compound obtained of general Formula I into an addition salt with an inorganic or organic acid.
- reactive esters of the allyl alcohol or 2-propin-1-ol particularly the halides such as the bromide, iodide and chloride, also alkane and arene sulphonic acid esters such as methane or p-toluene sulphonic acid esters, are used.
- the halides such as the bromide, iodide and chloride
- alkane and arene sulphonic acid esters such as methane or p-toluene sulphonic acid esters
- a mixture of abs. diethyl ether or tetrahydrofuran with 1,2-dimethoxyethane (ethylene glycol dimethyl ether) is suitable as reaction medium for the main reaction.
- the alkali metal compounds of general Formula IV are produced in situ from other suitable alkali metal compounds.
- Triphenylmethyl lithium which is particularly suitable as such, is also preferably formed in situ from another organic lithium compound such as phenyl lithium, for
- triphenylmethane in 1,2- dimethoxyethane
- triphenylmethyl lithium produces intensively coloured solutions, its formation as well as its use can be easily followed by the isonipecotonitrile which is subsequently added.
- triphenylmethyl sodium or potassium for example, can be useful instead of triphenylmethyl lithium.
- the steps in the processes according to the invention are generally slightly exothermic and can be performed at room temperature or slightly raised temperature. If necessary, the reaction mixture must also be able to be cooled depending on the starting materials and amounts thereof used.
- compounds of general Formula I wherein R is the allyl group, and their addition salts with inorganic and organic acids are produced by a third process by treating a compound of the restricted general .
- Formula V which is already embraced by general Formula I and in which R has the meaning given in Formula I, with hy drogen until the equimolar amount has been taken up, in the presence of a catalyst suitable for the partial hydrogenation of triple bonds.
- catalyst e.g., palladium on CaCO partially deactivated with lead acetate, in ethanol as solvent and further deactivated in situ by the addition of quinoline (Lindlar catalyst, cf. Helv. Chim. Acta 35, 450 (1952)), is used.
- the compound obtained of general Formula I is converted into an addition salt with an inorganic or organic acid.
- the piperidine derivatives of the general Formula I obtained by the processes according to the invention are then converted into their addition salts with inorganic and organic acids in the usual way.
- the acid desired as salt component or a solution thereof is added to a solution of a piperidine derivative of the general Formula I in an organic solvent such as diethyl ether, methanol or ethanol, and the salt which precipitates either direct or after addition of a second organic liquid, e.g. diethyl ether to methanol, is isolated.
- salts for use as active substances in therapeutic compositions, pharmaceutically acceptable acid addition salts can be used instead of free bases, i.e. salts with those acids the anions of which have no pharmacological action or which in themselves have a desired pharmacological action.
- salts to be used as active substances crystallise well and are not or are only slightly hygroscopic.
- Hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, fi-hydroxy-ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicyclic acid, phenylacetic acid, mandelic acid, embonic acid, or 1,5-naphthalene disulphonic acid, for example, can be used for salt formation with piperidine derivatives of the general Formula I.
- the new piperidine derivatives of the general Formula I and their salts may be administered orally, rectally or parenterally.
- the daily dosages of free bases or of pharmaceutically acceptable salts thereof vary between about 0.02 mg./kg. and about mg./kg., preferably about 0.05 mg./kg. to about 5.0 mg./kg. for mammals, depending on the mammal and condition.
- Suitable dosage units such as drages (sugar-coated tablets), capsules, tablets, suppositories or ampoules, preferably contain 1-100 mg. of piperidine derivative of the general Formula I or of a pharmaceutically acceptable salt thereof.
- Dosage units for oral administration preferably contain between 1% and of a piperidine derivative of general Formula I or of a pharmaceutically acceptable salt thereof as active substance. They are produced by combining the active substance with, e.g., solid, pulverulent carriers such as lactose sucrose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to form tablets or drage cores.
- solid, pulverulent carriers such as lactose sucrose, sorbitol, mannitol
- starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder
- cellulose derivatives or gelatine optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols
- the latter are coated, e.g., with concentrated sugar solutions which can also contain, e.g., gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents.
- Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.
- Other suitable dosage units for oral administration are hard gelatine capsules and also soft, closed capsules made of gelatine and a softener such as glycerin.
- the former preferably contain the active substance as a granulate in admixture with lubricants such as talcum or magnesium stearate and, optionally, stabilisers such as sodium metabisulphite or ascorbic acid.
- the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols to which stabilisers can also be added.
- lozenges for the treatment of coughs, e.g., lozenges as well as forms not made up into single dosages can be used for oral administration, e.g., cough syrups or drops prepared with the usual auxiliaries.
- Dosage units for rectal administration are, e.g., suppositories which consist of a combination of a piperidine derivative of the general Formula I or a suitable salt thereof with a neutral fatty foundation, or also gelatine rectal capsules which contain a combination of the active substance with polyethylene glycols.
- Ampoules for parenteral, particularly intramuscular, also intravenous, administration preferably contain a water-soluble salt of a piperidine derivative of the general Formula I as active substance in a concentration of, preferably, 0.5-5%, in aqueous solution, optionally together with suitable stabilisers and buffer substances.
- (c) 1,000 capsules each containing 10 mg. of active substance are produced as follows: 10 g. of 1-(2-pheny1- ethyl)-4-allyl isonipecotonitrile hydrochloride are mixed with 263 g. of lactose. The mixture is evenly moistened with an aqueous solution of 2 g. of gelatine and granulated through a suitable sieve (e.g. sieve III, Ph. Helv. V). The granulate is mixed with g. of dried maize starch and g. of talcum and is then evenly filled into 1,000 hard gelatine capsules, size 1.
- a suitable sieve e.g. sieve III, Ph. Helv. V
- a cough syrup containing 0.5% active substance is prepared as follows: 1.5 litres of glycerin, 42 g. of p-hydroxybenzoic acid methyl ester, 18 g. of p-hydroxybenzoic acid n-propyl ester and, while slightly warming, 50 g. of 1-(2-phenylethyl)-4-allyl isonipecotonitrile hydrochloride are dissolved in 3 litres of distilled water. 4 litres of 70% sorbitol solution, 1,000 g. of crystallised sucrose, 350 g. of glucose and a flavouring, e.g. 250 g. of Orange Peel Soluble Fluid produced by Ely Lilly & Co., Indianapolis, or 5 g. of natural lemon flavouring and 5 g. of Halb und Halb essence, both produced by Haarmann und Reimer, Holzminden, Germany, are added. The solution obtained is filtered and the filtrate is made up to 10 litres with distilled water.
- a cough syrup containing 0.25% of active substance is produced as follows: 25 g. of 1-(2-phenylethyl)- 4-allyl isonipecotonitrile hydrochloride is dissolved by warming in a mixture of 2.5 litres of water, and 0.5 litre of 96% ethanol. Also, a syrup is made from 30 litres of water, 1 litre of 70% sorbitol solution, 3,000 g. of crystallised sucrose, 42 g. of p-hydroxybenzoic acid methyl ester and 18 g. of p-hydroxybenzoic acid n-propyl ester, and this syrup is carefully mixed with the solution of active substance. After the addition of flavourings, e.g. those mentioned under (d) and, if necessary, filtration, the syrup obtained is made up to 10 litres with distilled Water.
- flavourings e.g. those mentioned under (d) and, if necessary, filtration
- drops containing 2.5% of active substance are prepared by dissolving 250 g. of 1-(2-phenylethyl)-4-allyl isonipecotonitrile hydrochloride and 30 g. of sodium cyclamate in a mixture of 4 litres of 96% ethanol and 1 litre of propylene glycol. Also, 3.5 litres of 70% sorbitol solution are mixed with 1 litre of water and this mixture is added to the above solution of active substance.
- a mass for suppositories is made from 2.5 g. of 1-(2-phenylethyl)-4-allyl isonipecotonitrile hydrochloride and 167.5 g. of Adeps solidus and 100 suppositories are filled therewith. Each contain 25 mg. of active substance.
- EXAMPLE 2 4.5 g. of bromobenzene in 60 ml. of abs. ether are placed in a 200 ml. four-necked flask and, while stirring under an atmosphere of nitrogen, 0.40 g. of lithium wire cut into small pieces are added whereupon the ether be gins to boil. After the reaction has subsided the mixture is refluxed for another 2 /2 hours. 6.35 g. of triphenylmethane in 25 ml. of abs. 1,2-di-methoxyethane are added all at once to the solution of phenyl lithium obtained whereupon, due to the formation of triphenylmethyl lithium, the solution turns deep red and gently boils. After stirring for 20 minutes at room temperature, 5.5 g.
- the acid extracts are made alkaline and exhaustively extracted with chloroform.
- the chloroform extracts are dried and concentrated.
- the residue is taken up in ether, the ether solution is dried and concentrated and the residue is distilled.
- the 1-(2 phenylethyl)-4-allyl isonipecotonitrile boils at 126-139/0.2 torr.
- the hydrochloride prepared with hydrogen chloride in ether melts, after recrystallisation from methanol, at M.P. 293294.
- the starting material is produced as follows:
- Ether is added to the residue and the ether solution obtained is extracted four times with dilute hydrochloric acid.
- the acid extracts are made alkaline ond exhaustively extracted with chloroform.
- the chloroform extracts are dried and evaporated.
- the residue is taken up in ether, the ether solution is dried and concentrated and the residue is distilled.
- the 1-(2-phenylethyl)-4(2-propinyl)-isonipecotonitrile passes over at 141-170/ 0.05 torr.
- the hydrochloride is produced therefrom in ether and recrystallised from isopropanol/methanol.
- EXAMPLE 4 A solution of 2.52 g. of l-(2-phenylethyl)-4-(2- propinyl)-isonipecotonitrile in 50 ml. of ethanol is hydrogenated at room temperature under normal pressure in the presence of 0.5 g. of Lindlar catalyst (palladium on calcium carbonate, partially deactivated with lead acetate) and 0.2 g. of quinoline. After about 107% of the theoretically necessary amount of hydrogen has been taken up, the hydrogenation is discontinued, the catalyst is filtered off and thoroughly washed with ethanol. The filtrate is evaporated in a rotary evaporator and the residue is distilled under high vacuum.
- Lindlar catalyst palladium on calcium carbonate, partially deactivated with lead acetate
- the l-(2-phenylethyl)-4- allyl isonipecotonitrile obtained boils at l26-139/0.2 torr.
- the hydrochloride prepared with hydrogen chloride is recrystallised from methanol whereupon it melts at 293-294".
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO16881567 | 1967-06-28 | ||
NO16881667 | 1967-06-28 | ||
CH42068A CH491915A (de) | 1967-06-28 | 1968-01-11 | Verfahren zur Herstellung von neuen Piperidinderivaten |
Publications (1)
Publication Number | Publication Date |
---|---|
US3551431A true US3551431A (en) | 1970-12-29 |
Family
ID=27172088
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US739194A Expired - Lifetime US3551431A (en) | 1967-06-28 | 1968-06-24 | Isonipecotonitriles |
Country Status (8)
Country | Link |
---|---|
US (1) | US3551431A (enrdf_load_stackoverflow) |
BE (1) | BE717270A (enrdf_load_stackoverflow) |
CH (1) | CH491915A (enrdf_load_stackoverflow) |
ES (1) | ES355551A1 (enrdf_load_stackoverflow) |
FR (2) | FR1596472A (enrdf_load_stackoverflow) |
GB (1) | GB1231081A (enrdf_load_stackoverflow) |
IL (1) | IL30265A0 (enrdf_load_stackoverflow) |
NL (1) | NL6808702A (enrdf_load_stackoverflow) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4870086A (en) * | 1986-01-03 | 1989-09-26 | Astra Lakemedel Aktiebolag | Optically pure compound and a process for its preparation |
US20040071797A1 (en) * | 2002-10-09 | 2004-04-15 | Dennis Donald P. | Method and formulation for suppressing mold |
US10150731B2 (en) * | 2015-01-16 | 2018-12-11 | Bayer Cropscience Aktiengesellschaft | Method for preparing 4-cyanopiperidine hydrochloride |
-
1968
- 1968-01-11 CH CH42068A patent/CH491915A/de not_active IP Right Cessation
- 1968-06-20 NL NL6808702A patent/NL6808702A/xx unknown
- 1968-06-24 US US739194A patent/US3551431A/en not_active Expired - Lifetime
- 1968-06-27 IL IL30265A patent/IL30265A0/xx unknown
- 1968-06-27 FR FR1596472D patent/FR1596472A/fr not_active Expired
- 1968-06-27 GB GB1231081D patent/GB1231081A/en not_active Expired
- 1968-06-27 ES ES355551A patent/ES355551A1/es not_active Expired
- 1968-06-27 BE BE717270D patent/BE717270A/xx unknown
- 1968-08-23 FR FR163953A patent/FR7917M/fr not_active Expired
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4870086A (en) * | 1986-01-03 | 1989-09-26 | Astra Lakemedel Aktiebolag | Optically pure compound and a process for its preparation |
US20040071797A1 (en) * | 2002-10-09 | 2004-04-15 | Dennis Donald P. | Method and formulation for suppressing mold |
US10150731B2 (en) * | 2015-01-16 | 2018-12-11 | Bayer Cropscience Aktiengesellschaft | Method for preparing 4-cyanopiperidine hydrochloride |
Also Published As
Publication number | Publication date |
---|---|
CH491915A (de) | 1970-06-15 |
FR1596472A (enrdf_load_stackoverflow) | 1970-06-22 |
GB1231081A (enrdf_load_stackoverflow) | 1971-05-05 |
FR7917M (enrdf_load_stackoverflow) | 1970-05-11 |
NL6808702A (enrdf_load_stackoverflow) | 1968-12-30 |
ES355551A1 (es) | 1970-03-01 |
BE717270A (enrdf_load_stackoverflow) | 1968-12-27 |
IL30265A0 (en) | 1968-08-22 |
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